Project Summary/Abstract The goals of this project are 1) to understand the multifaceted interaction of NREM sleep continuity and aging on synapse and memory function, and 2) to serve as a platform to facilitate and develop my independent research by combining my expertise in synapse plasticity and sleep with training in the fields of aging, neurodegeneration and optogenetics. There is strong support that NREM continuity plays a critical role in synaptic plasticity and memory function. Moreover, NREM continuity is increasing disrupted in aging humans. However, it is unknown how NREM mediated synaptic plasticity interact with aging induced cognitive decline. My preliminary results, using a novel proteomic synapses analysis method, suggest that aging decreases cortical synapse density, and sleep mediates circuit level structural plasticity through synapse elaboration and single synapse level homeostatic downscaling, where the average synapse size and receptor composition is reduced. Interestingly, my analysis also revealed a correlation between A? accumulation and sleep, in which, wake appears to elevate levels of A? in specific subsets of synapses, while sleep mediates a reduction of synaptic A?. Together, the data suggest that synapse and circuit optimization during sleep occurs on many levels. On the circuit level new synapses are generated, which strengthens previous connections and memories, and provides fertile new substrate for new memory formation. On the single synapse level, sleep homeostatic pressure drives the downscaling of synapses to remove unnecessary synaptic connections. Finally, on a metabolic level, built-up factors, such as A?, are cleared from metabolically active synapses. I hypothesize that aging likely disrupts these aspects of sleep differentially. The decreased synapse density I have seen thus far in aged mice cortex, would suggest that circuit level synapse generation could be suppressed in older animals, while NREM homeostatic downscaling remained intact. This imbalance could lead to a gradual decrease in synapse density, and imply that in aged adults new memory formation would likely be more difficult, but retention should not be affected. However, little is known about how aging impacts the synaptic landscape of the brain and whether that impact affects the synaptic function of sleep. The aims of this project are to provide data in: 1) revealing the global molecular changes in the synaptic landscape mediated by aging, and reveal how NREM sleep interacts with these changes. 2) The specific synapses and neurons involved in A? synapse accumulation and release. 3) The molecular actors involved in NREM mediated A? synapse clearance; and 4) Correlating synapse molecular changes with functional acquisition and retention of memories in young and old adult mice. The data from this research will be a first system level description of molecular changes in synapses during aging and sleep. Moreover, results of this study could significantly impact our understanding of sleep intervention in the treatment of cognitive decline in normal and pathological aging. The proposed research and training will be for a junior faculty level position lasting 5 years.